Chris Miller is in the Department of Basic and Clinical Neuroscience
Work in our research group aims to understand better the molecular mechanisms that underlie neuronal cell death in neurodegenerative diseases. We are studying Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis with associated fronto-temporal dementia (FTD/ALS). These disorders display many common pathogenic features. We are particularly interested in how defects in signal transduction contribute to the neurodegenerative process.
We are studying protein and organelle trafficking in neurons since these processes are disrupted in Alzheimer’s and Parkinson’s diseases, and in FTD/ALS. Notably, transport of cargoes through axons (axonal transport) is one of the earliest pathological features in these disorders. The early damage to axonal transport argues that it contributes to the disease process in a primary fashion. In particular, we have been investigating axonal transport of the amyloid precursor protein (APP) and mitochondria. APP is a key cargo in Alzheimer’s disease since disruption to its transport affects how it is processed to produce Abeta and Alzheimer’s disease insults affect APP transport. We have identified a new mechanism involving calsyntenin-1 and X11beta by which APP attaches to kinesin-1 motors for transport. We have also identified a new signalling pathway involving lemur tyrosine kinase-2 that regulates GSK-3beta activity and axonal transport. GSK-3beta is strongly implicated in Alzheimer’s disease.
Mitochondria are another key cargo since they are essential for synaptic function; synaptic transmission requires huge amounts of ATP. Loss of synapses is an underlying feature of neurodegenerative diseases and a considerable body of evidence implicates damage to mitochondrial function in neurodegenerative diseases. We have identified mechanisms involving changes to calcium homeostasis by which some ALS insults disrupt mitochondrial transport.
Finally, we are investigating how communications between mitochondria and the endoplasmic reticulum (ER) impact upon the neurodegenerative process. Mitochondria and ER form close physical associations and these regulate a number of fundamental physiological processes including ATP production, ER stress, lipid metabolism, calcium homeostasis, mitochondrial biogenesis, axonal transport, autophagy and inflammation. Many of these processes are perturbed in neurodegenerative diseases. Recently, we identified a mechanism by which regions of ER come form contacts with mitochondria. It involves binding of the integral ER protein VAPB to the outer mitochondrial membrane protein PTPIP51 which together form a “molecular scaffold” that tethers ER to mitochondria. We have also shown that some FTD/ALS insults break the VAPB-PTPIP51 tethers to loosen ER-mitochondria associations. These findings reveal a new pathogenic process for FTD/ALS. We are utilizing this information to build cellular screens to identify small molecules that might correct damaged ER-mitochondria contacts in disease. We anticipate that such molecules will represent novel therapeutics.